Fe(iii)-pyrazine complex compounds for treatment and prophylaxis of iron-deficiency phenomena and iron-deficiency anaemia

ABSTRACT

The invention relates to iron(III) complex compounds and pharmaceutical compositions comprising them for the use as medicaments, in particular for the treatment and/or prophylaxis of iron deficiency symptoms and iron deficiency anemias.

INTRODUCTION

The invention relates to iron(III)-pyrazine-2-ol-1-oxide complexcompounds and pharmaceutical compositions comprising them for the use asmedicaments, in particular for the treatment and/or prophylaxis of irondeficiency symptoms and iron deficiency anemias.

BACKGROUND

Iron is an essential trace element for almost all organisms and isrelevant in particular with respect to growth and the formation ofblood. The balance of the iron metabolism is in this case primarilyregulated on the level of iron recovery from hemoglobin of ageingerythrocytes and the duodenal absorption of dietary iron. The releasediron is taken up via the intestine, in particular via specific transportsystems (DMT-1, ferroportin, transferrin, transferrin receptors),transferred into the circulation and thereby conveyed to the appropriatetissues and organs.

In the human body, the element iron is of great importance for oxygentransport, oxygen uptake, cell functions such as mitochondrial electrontransport, and ultimately for the entire energy metabolism.

On average, the human body contains 4 to 5 g iron, with it being presentin enzymes, in hemoglobin and myoglobin, as well as depot or reserveiron in the form of ferritin and hemosiderin.

Approximately half of this iron, about 2 g, is present as heme iron,bound in the hemoglobin of the erythrocytes. Since these erythrocyteshave only a limited lifespan (75-150 days), new ones have to be formedconstantly and old ones eliminated (over 2 million erythrocytes arebeing formed per second). This high regenerative capacity is achieved bymacrophages phagocytizing the ageing erythrocytes, lysing them and thusrecycling the iron thus obtained for the iron metabolism. The amount ofiron of about 25 mg required daily for erythropoiesis is thus providedfor the main part.

The daily iron requirement of an adult human is between 0.5 to 1.5 mgper day, infants and women during pregnancy require 2 to 5 mg of ironper day. The daily iron loss, e.g. by desquamation of skin andepithelial cells, is low; increased iron loss occurs, for example,during menstrual hemorrhage in women. Generally, blood loss cansignificantly reduce the iron level since about 1 mg iron is lost per 2ml blood. In a healthy human adult, the normal daily loss of iron ofabout 1 mg is usually replaced via the daily food intake. The iron levelis regulated by absorption, with the absorption rate of the iron presentin food being between 6 and 12%; in the case of iron deficiency, theabsorption rate is up to 25%. The absorption rate is regulated by theorganism depending on the iron requirement and the size of the ironstore. In the process, the human organism utilizes both divalent as wellas trivalent iron ions. Usually, iron(III) compounds are dissolved inthe stomach at a sufficiently acid pH value and thus made available forabsorption. The absorption of the iron is carried out in the upper smallintestine by mucosal cells. In the process, trivalent non-heme iron isfirst reduced in the intestinal cell membrane to Fe(II) for absorption,for example by ferric reductase (membrane-bound duodenal cytochrome b),so that it can then be transported into the intestinal cells by means ofthe transport protein DMT1 (divalent metal transporter 1). In contrast,heme iron enters the enterocytes through the cell membrane without anychange. In the enterocytes, iron is either stored in ferritin as depotiron, or discharged into the blood by the transport protein ferroportin.Hepcidin plays a central role in this process because it is the mostimportant regulating factor of iron uptake. The divalent irontransported into the blood by ferroportin is converted into trivalentiron by oxidases (ceruloplasmin, hephaestin), the trivalent iron thenbeing transported to the relevant places in the organism by transferrin(see for example “Balancing acts: molecular control of mammalian ironmetabolism”. M. W. Hentze, Cell 117, 2004, 285-297.)

Mammalian organisms are unable to actively discharge iron. The ironmetabolism is substantially controlled by hepcidin via the cellularrelease of iron from macrophages, hepatocytes and enterocytes.

In pathological cases, a reduced serum iron level leads to a reducedhemoglobin level, reduced erythrocyte production and thus to anemia.

External symptoms of anemias include fatigue, pallor as well as reducedcapacity for concentration. The clinical symptoms of an anemia includelow serum iron levels (hypoferremia), low hemoglobin levels, lowhematocrit levels as well as a reduced number of erythrocytes, reducedreticulocytes and elevated levels of soluble transferrin receptors.

Iron deficiency symptoms or iron anemias are treated by supplying iron.In this case, iron substitution takes place either orally or byintravenous iron administration. Furthermore, in order to boosterythrocyte formation, erythropoietin and othererythropoiesis-stimulating substances can also be used in the treatmentof anemias.

Anemia can often be traced back to malnutrition or low-iron diets orimbalanced nutritional habits low in iron. Moreover, anemias occur dueto reduced or poor iron absorption, for example because ofgastroectomies or diseases such as Crohn's disease. Moreover, irondeficiency can occur as a consequence of increased blood loss, such asbecause of an injury, strong menstrual bleeding or blood donation.Furthermore, an increased iron requirement in the growth phase ofadolescents and children as well as in pregnant women is known. Sinceiron deficiency not only leads to a reduced erythrocyte formation, butthereby also to a poor oxygen supply of the organism, which can lead tothe above-mentioned symptoms such as fatigue, pallor, reduced powers ofconcentration, and especially in adolescents, to long-term negativeeffects on cognitive development, a highly effective and well toleratedtherapy is of particular interest.

Through using the Fe(III) complex compounds according to the invention,there is the possibility of treating iron deficiency symptoms and irondeficiency anemias effectively by oral application without having toaccept the large potential for side effects of the classicalpreparations, the Fe(II) iron salts, such as FeSO4, which is caused byoxidative stress. Poor compliance, which often is the reason for thedeficient elimination of the iron deficiency condition, is thus avoided.

PRIOR ART

A multitude of iron complexes for the treatment of iron deficiencyconditions is known from the prior art.

A very large proportion of these complex compounds consists of polymerstructures. Most of these complex compounds are iron-polysaccharidecomplex compounds (WO20081455586, WO2007062546, WO20040437865,US2003236224, EP150085). It is precisely from this area that there aremedicaments available on the market (such as Maltofer, Venofer,Ferinject, Dexferrum, Ferumoxytol).

Another large portion of the group of the polymer complex compounds iscomprised of the iron-peptide complex compounds (CN101481404, EP939083,JP02083400).

There are also Fe complex compounds described in the literature that arestructurally derived from macromolecules such as hemoglobin,chlorophyll, curcumin and heparin (US474670, CN1687089, Biometals, 2009,22, 701-710).

Moreover, low-molecular Fe complex compounds are also described in theliterature. A large number of these Fe complex compounds comprisescarboxylic acid and amino acids as ligands. In this case, the focus ison aspartate (US2009035385) and citrate (EP308362) as ligands. Fecomplex compounds containing derivatized phenylalanine groups as ligandsare also described in this context (ES2044777).

Hydroxypyrone and hydroxypyridone Fe complex compounds are alsodescribed in the literature (EP159194, EP138420, EP107458, EP0120670).The corresponding 5-ring systems, the hydroxyfuranone Fe complexcompounds, are also described in analogy thereto (WO2006037449). Inparticular, the hydroxypyridone Fe complex compounds, however, havecomparatively low water solubility, making them less suitable,especially for oral administration. Furthermore the hydroxypyridone Fecomplex compounds have comparatively low iron utilization.

INTERNATIONAL JOURNAL FOR VITAMIN AND NUTRITION RESEARCH, 77(1), 13-21CODEN: IJVNAP; ISSN: 0300-9831, 2007 describes ferrichrysines for theuse in the treatment of iron deficiency diseases.

Moreover, iron-cyclopentadienyl complex compounds are also described inthe literature (GB842637).

Furthermore, 1-hydroxy-2(1H)-pyrazinone (HOPR—H) and1-hydroxy-5,6-dimethyl-2(1H)-pyrazinone (HOPR-Me) have been described(Bull. Chem. Soc. Jpn., 66, 841-841(1993); see also “Reviews OnHeteroatom Chemistry”, Vol. 18, 1998, page 87 to 118 and TETRAHEDRON,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, Vol. 51, No. 47, Nov. 20,1995 (1995-11-20), pages 12995-13002 from the same authors). For thelatter compound, the UV-vis spectrum of a 3:1 molar mixture with iron(III) is shown in an aqueous solution at various pH conditions. From theexperiments the formation of 3:1-complexes with iron (III) is concluded.In contrast as to the pyrimidinones no possible structure of thepyrazinone-complex compounds is shown. An isolation of the iron complexcompounds from the 3:1 mixtures in aqueous solution was not carried out.Accordingly, no solid iron complex compounds have been isolated ordisclosed. Furthermore, the iron complex compounds are not proposed asmedicaments, such as especially for the treatment of iron deficiencysymptoms. The same authors suggest only the use of hexadentate1-hydroxy-1H-pyrazine-2-one compounds as iron sequestering agents fortreatment of iron overload conditions such as thalassemia (J. Org. Chem.1997, 62, 3618-3624). By the administration of hydroxy-pyrimidinone or-pyrazine compounds to the body for the treatment of thalassemia ironmight be removed—so no iron will be supplied—as in the treatment of irondeficiency anemia by administration of iron complex compounds inaccordance with the present invention.

J. Am. Chem. Soc. 1985, 107, 6540-6546 describes tetradentate1-hydroxy-1H-pyridine-2-one compounds as ligands and a binuclear ironcomplex compound therewith. The possibility to use the ligands for ironsequestering is mentioned, too. Similarly, Inorganica Chimica Acta, 135(1987) 145-150 discloses the use of 1-hydroxy-1H-pyridine-2-ones asagents for masking iron.

NATURAL PRODUCT COMMUNICATIONS; 2011, 6(8), 1137-1140 and Journal ofAgricultural and Food Chemistry, Jan. 1, 1981 (1981-01-01), pages785-787 describe iron (III)-complexes of neoaspergillinic acid, whereinthe first mentioned publication further generally mentions theantibacterial activity thereof. Chemical & Pharmaceutical Bulletin, Jan.1, 1978 (1978-01-01), pages 1320-1322 describes structurally similariron complex compounds. The use of such iron complexes as medicaments,such as especially in the treatment of iron deficiency anemia is notmentioned.

Chemical & Pharmaceutical Bulletin, Jan. 1, 1994 (1994-01-01), pages277-279, Chemical & Pharmaceutical Bulletin, Jan. 1, 1981 (1981-01-01),pages 1510-1517 and HETEROCYCLES, ELSEVIER SCIENCE PUBLISHERS B.V.AMSTERDAM, NL, Vol. 35, No. 2, Jan. 1, 1993 (1993-01-01), pages1279-1287 describe astechrome and its isolation as a metabolic productof Aspergillus strains. The use of such iron complexes as medicaments,such as especially in the treatment of iron deficiency anemia is notmentioned.

Iron salts (e.g. iron(II) sulfate, iron(II) fumarate, iron(III)chloride, iron(II) aspartate, iron(II) succinate) are another importantconstituent for the treatment of iron deficiency symptoms and irondeficiency anemias.

These iron salts are very problematic in that, in part, they are highlyincompatible (up to 50%) in the form of nausea, vomiting, diarrhea andalso obstipation and cramps. Moreover, free iron(II) ions which catalyzethe formation (inter alia Fenton reaction) of reactive oxygen species(ROS) occur during the use of these iron(II) salts. These ROS causedamage to DNA, lipids, proteins and carbohydrates which has far-reachingeffects in cells, tissue and organs. This complex of problems is knownand, in the literature, is largely considered the cause for the highincompatibility and referred to as oxidative stress.

Therefore, iron(III)-1-hydroxy-1H-pyrazine-2-one orpyrazine-2-ol-1-oxide complex compounds, respectively, have not beendescribed in the prior art neither as a medicament nor in particular forthe use in the treatment and/or for prophylaxis of iron deficiencysymptoms and iron deficiency anemia so far.

Object

The object of the present invention lay in developing newtherapeutically effective compounds that can be used for an effectivetherapy for the preferably oral treatment of iron deficiency symptomsand iron deficiency anemias. In this case, these iron complexes weresupposed to exhibit significantly fewer side effects than theclassically used Fe(II) salts. Furthermore, these iron complexes, incontrast to the known polymeric iron complex compounds, were, ifpossible, supposed to have a defined structure (stoichiometry) and bepreparable by simple synthesis processes. In addition, the compoundsshould effect a high iron utilization rate upon oral administration,which is supported by a good water solubility. Finally, the iron complexcompounds should have a very low toxicity and can be thereforeadministered in very high dosages. This goal was achieved by thedevelopment of novel Fe(III) complex compounds.

Furthermore, the novel iron complexes were supposed to be designed suchthat they are taken up into the intestinal cells directly via themembrane in order thus to release their complex-bound iron directly tothe ferritin or the transferrin or to reach the bloodstream directly asan intact complex. Because of their properties, these new complexes aresupposed to virtually not lead to the occurrence of high concentrationsof free iron ions. For it is precisely the free iron ions that lead tothe occurrence of ROS which are ultimately responsible for the sideeffects that occur.

In order to be able to meet these requirements, the inventors developednew Fe(III) complex compounds with a molecular weight that is not toolarge, medium lipophila and an optimal complex stability.

DESCRIPTION OF THE INVENTION

The inventors surprisingly found that Fe(III) complex compounds withpyrazine-2-ol 1-oxide were particularly suitable for the above-describedrequirements. It was possible to demonstrate that these Fe complexcompounds exhibited a high iron uptake, whereby a quick therapeuticsuccess in the treatment of iron deficiency anemia could be achieved.Especially in comparison to iron salts, the complex compounds accordingto the invention exhibited a faster and higher utilization. Furthermore,these new systems have significantly reduced side effects than theclassically used iron salts since there is no noteworthy occurrence offree iron irons in this case. The complex compounds according to theinvention exhibit almost no oxidative stress since there is no formationof free radicals. Thus, significantly fewer side effects occur in thecase of these complex compounds than in the case of the Fe salts knownfrom the prior art. The complex compounds exhibit good stability atvarious pH value ranges and comparably good solubility. Furthermore, theiron complex compounds have a very low toxicity and can therefore beadministered in high dosages without side effects. Finally the complexcompounds can be prepared well and are optimally suitable for theformulation of medicaments, in particular for oral administration.

Thus, the subject matter of the invention areiron(III)-pyrazine-2-ol-1-oxide complex compounds or theirpharmaceutically acceptable salts for use as medicaments or synonymousfor use in a method for therapeutic treatment of the human body,respectively.

The iron(III)-pyrazine-2-ol-1-oxide complex compounds as used inaccordance with the present invention particularly include suchcompounds which comprise the following structural element:

wherein

respectively is a substituent of the ligand saturating the free valenceand the arrows respectively represent coordinate bonds to the iron atom.

The terms

-   -   “pyrazine-2-ol-1-oxide”,    -   “pyrazine-2-ol-1-oxide compounds” or    -   “pyrazine-2-ol-1-oxide-” ligands        according to the invention include the corresponding hydroxy        starting compounds

as well as the corresponding deprotonated ligands

respectivelywhich are present in the corresponding iron(III) complex compounds.

Furthermore, according to the invention the aforementioned terms do notonly comprise the respective base body:

or the ligand compound resulting from deprotonating the underlyinghydroxy compound

respectivelybut as well their representatives substituted on the pyrimidine rings,resulting from the replacement of one or more hydrogen atoms on thepyrazine ring by other substituents. Accordingly, in context with thepresent invention the aforementioned terms refer to the entire class of“pyrazine-2-ol-1-oxide” compounds and the deprotonated ligands,including their representatives substituted on the pyrazine ring.

Formally, a (deprotonated) pyrazine-2-ol-1-oxide ligand according to thepresent invention carries a negative charge. This means, that in thecase of three ligands per iron atom, the iron atom formally has theoxidation state +3. It is clear to the person skilled in the art thatthe shown formulas represent only one possible mesomeric formula andthat there are several mesomeric formulas and that delocalisation of theelectrons in the ligands or in the iron complex compound may be present,respectively, as shown hereinafter schematically.

In the iron(III) pyrazine-2-ol-1-oxide complex compounds according tothe invention, the coordination number of the iron atoms is generallysix (6), with a coordinating atoms generally being arrangedoctahedrally.

Furthermore, mono- or polynuclear iron(III) pyrazine-2-ol-1-oxidecomplex compounds in which one or more (such as 2, 3 or 4) iron atomsare present are also comprised according to the invention.

Generally, 1-4 iron atoms and 2-10 ligands can be present in theiron(III) pyrazine-2-ol-1-oxide complex compounds. Mononuclear iron(III)pyrazine-2-ol-1-oxide complex compounds with at least one preferablytri-, preferably bidentate pyrazine-2-ol-1-oxide ligands are preferred.Mononuclear iron(III) pyrazine-2-ol-1-oxide complex compounds with one(1) central iron atom and three (3) pyrazine-2-ol-1-oxide ligands areparticularly preferred.

The iron(III) pyrazine-2-ol-1-oxide complex compounds of the presentinvention are generally present in neutral form. However, salt likeiron(III) pyrazine-2-ol-1-oxide complex compounds are also included, inwhich the complex has a positive or negative charge which iscompensated, in particular, by pharmacologically compatible,substantially non-coordinating anions (such as, in particular,halogenides, such as chloride) or cations (such as, in particular,alkaline or alkaline-earth metal ions).

The iron(III) pyrazine-2-ol-1-oxide complex compounds according to theinvention particularly include complex compounds, comprising at leastone, preferably a bidentate pyrazine-2-ol-1-oxide ligand of the formula

wherein

respectively is a substituent saturating the free valence of theligands, which can, as shown above, bond to one or even two differentiron atoms in the sense of bridging.

Iron(III) pyrazine-2-ol-1-oxide complex compounds are preferred whichexclusively comprise preferably bidentate pyrazine-2-ol-1-oxide ligandswhich may be the same or different. Furthermore, iron(III)pyrazine-2-ol-1-oxide complex compounds are particularly preferred whichexclusively comprise the same pyrazine-2-ol-1-oxide ligands and veryparticularly preferred are tris(pyrazine-2-ol-1-oxide) iron(III)compounds.

Preferably, the molecular weight of the inventive iron(III)-pyrazine-2-ol 1-oxide-complex compounds is less than 1000 g/mol,more preferably less than 800 g/mol (each determined from the structuralformula).

In a particularly preferred embodiment the iron(III) complex compoundsaccording to the present invention comprise at least one, preferablythree same or different, preferably same ligands of the formula (I):

wherein

-   the arrows respectively represent a coordinate bond to one or    different iron atoms, and-   R₁, R₂, R₃ may be the same or different and are selected from the    group consisting of:    -   hydrogen,    -   optionally substituted alkyl,    -   halogen,    -   optionally substituted alkoxy,    -   optionally substituted aryl,    -   optionally substituted alkoxycarbonyl, and    -   optionally substituted aminocarbonyl or-   R₂ and R₃ together with the carbon atoms to which they are bonded,    form an optionally substituted saturated or unsaturated 5- or    6-membered ring, which may optionally contain one or more    heteroatoms, or pharmaceutically acceptable salts thereof.

The above-mentioned ring formation of the substituents R₂ and R₃ isschematically shown in the following formula:

Therein, R₁ can have one of the mentioned meanings.

A preferred embodiment of the present invention relates to theseiron(III) complex compounds containing at least one ligand of theformula (I):

wherein

-   the arrows respectively represent a coordinate bond to one or    different iron atoms, and-   R₁, R₂, R₃ may be the same or different and are selected from the    group consisting of:    -   hydrogen, and    -   optionally substituted alkyl.

Within the overall context of the invention, optionally substitutedalkyl, in particular for the substituents R₁ to R₃, preferably includes:

straight-chained or branched alkyl with 1 to 8, preferably 1 to 6 carbonatoms, cycloalkyl with 3 to 8, preferably 5 or 6 carbon atoms, or alkylwith 1 to 4 carbon atoms, which is substituted with cycloalkyl, whereinthese alkyl groups can be optionally substituted.

The above mentioned alkyl groups can be unsubstituted or substituted,preferably with 1 to 3 substituents. These substituents at the alkylgroups are preferably selected from the group consisting of: hydroxy,optionally substituted aryl, in particular as defined below, optionallysubstituted heteroaryl, in particular as defined below, optionallysubstituted alkoxy, in particular as defined below, optionallysubstituted alkoxycarbonyl, in particular as defined below, optionallysubstituted acyl, in particular as defined below, halogen, in particularas defined below, optionally substituted amino, in particular as definedbelow, optionally substituted aminocarbonyl, in particular as definedbelow, and cyano.

Halogen includes here and within to the context of the presentinvention, fluorine, chlorine, bromine and iodine, preferably fluorineor chlorine.

In the above defined alkyl groups, optionally one or more, morepreferably 1 to 3 carbon atoms can furthermore be replaced withhetero-analogous groups that contain nitrogen, oxygen or sulphur. Thismeans, in particular, that, for example, one or more, preferably 1 to 3,still more preferred one (1) methylene group (—CH₂—) can be replaced inthe alkyl groups by —NH—, —NR₄—, —O— or —S—, wherein R₄ is optionallysubstituted alkyl as defined above, preferably optionally substitutedwith 1 to 3 substituents, such as fluorine, chlorine, hydroxy or alkoxy,substituted C₁-C₆ alkyl, such as methyl or ethyl.

Examples of alkyl residues having 1 to 8 carbon atoms include: a methylgroup, an ethyl group, an n-propyl group, an i-propyl group, an n-butylgroup, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentylgroup, an i-pentyl group, a sec-pentyl group, a t-pentyl group, a2-methylbutyl group, a n-hexyl group, a 1-methylpentyl group, a2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a1-ethylbutyl group, a 2-ethylbutyl group, a 3-ethylbutyl group, a1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutylgroup, a 1-ethyl-1-methylpropyl group, a n-heptyl group, a 1-methylhexylgroup, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexylgroup, a 5-methylhexyl group, a 1-ethylpentyl group, a 2-ethylpentylgroup, a 3-ethylpentyl group, a 4-ethylpentyl group, a1,1-dimethylpentyl group, a 2,2-dimethylpentyl group, a3,3-dimethylpentyl group, a 4,4-dimethylpentyl group, a 1-propylbutylgroup, an n-octyl group, a 1-methylheptyl group, a 2-methylheptyl group,a 3-methylheptyl group, a 4-methylheptyl group, a 5-methylheptyl group,a 6-methylheptyl group, a 1-ethylhexyl group, a 2-ethylhexyl group, a3-ethylhexyl group, a 4-ethylhexyl group, a 5-ethylhexyl group, a1,1-dimethylhexyl group, a 2,2-dimethylhexyl group, a 3,3-dimethylhexylgroup, a 4,4-dimethylhexyl group, a 5,5-dimethylhexyl group, a1-propylpentyl group, a 2-propylpentyl group, etc. Those with 1 to 6carbon atoms are preferred. Methyl, ethyl, n-propyl, isopropyl,sec-butyl and n-butyl are most preferred.

Examples of alkyl groups produced by replacement with one or morehetero-analogous groups, such as —O—, —S—, —NH— or —N(R₄)— arepreferably such groups in which one or more methylene groups (—CH₂—) arereplaced with —O— while forming an ether group, such as methoxymethyl,ethoxymethyl, 2-methoxyethyl etc. Therefore, the definition of alkylalso includes, for example, alkoxyalkyl groups as defined below, whichare produced from the above-mentioned alkyl groups by replacement of amethylene group with —O—. If, according to the invention, alkoxy groupare additionally permitted as substituents of alkyl, several ethergroups can also be formed in this manner (such as a—CH₂—O—CH₂—OCH₃-group). Thus, according to the invention, polyethergroups are also comprised by the definition of alkyl.

Cycloalkyl groups with 3 to 8 carbon atoms preferably include: acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup, a cycloheptyl group, a cyclooctyl group, etc. A cyclopropylgroup, a cyclobutyl group, a cyclopentyl group and a cyclohexyl groupare preferred. The cycloalkyl groups may optionally be substitutedpreferably with 1 to 2 substituents such as hydroxyl or C₁-C₆alkoxycarbonyl.

The definition of the optionally substituted alkyl also includes alkylgroups which are substituted by the above mentioned cycloalkyl groups,such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl orcyclohexylmethyl.

Heterocyclic alkyl groups according to the invention are preferablythose formed by the replacement of methylene with hetero-analogousgroups from cycloalkyl, and include, for example, saturated 5 or6-membered heterocyclic residues, which may be attached via a carbonatom or a nitrogen atom, and which preferably may have 1 to 3,preferably 2 heteroatoms, especially O, N, such as tetrahydrofuryl,azetidine-1-yl, substituted azetidinyl, such as 3-hydroxyazetidin-1-yl,pyrrolidinyl, such as pyrrolidin-1-yl, substituted pyrrolidinyl, such as3-hydroxypyrrolidin-1-yl, 2-hydroxypyrrolidin-1-yl2-methoxycarbonylpyrrolidin-1-yl, 2-ethoxycarbonylpyrrolidin-1-yl,2-methoxypyrrolidin-1-yl, 2-ethoxypyrrolidin-1-yl,3-methoxycarbonylpyrrolidin-1-yl, 3-ethoxycarbonylpyrrolidin-1-yl,3-methoxypyrrolidin-1-yl, 3-ethoxypyrrolidine-1-yl, piperidinyl, such aspiperidin-1-yl, piperidin-4-yl, substituted piperidinyl, such as4-methyl-1-piperidyl, 4-hydroxy-1-piperidyl, 4-methoxy-1-piperidyl,4-ethoxy-1-piperidyl, 4-methoxycarbonyl-1-piperidyl,4-ethoxycarbonyl-1-piperidyl, 4-carboxy-1-piperidyl,4-acetyl-1-piperidyl, 4-formyl-1-piperidyl, 1-methyl-4-piperidyl,4-hydroxy-2,2,6,6-tetramethyl-1-piperidyl,4-(dimethylamino)-1-piperidyl, 4-(diethylamino)-1-piperidyl,4-amino-1-piperidyl, 2-(hydroxymethyl)-1-piperidyl,3-(hydroxymethyl)-1-piperidyl, 4-(hydroxymethyl)-1-piperidyl,2-hydroxy-1-piperidyl, 3-hydroxy-1-piperidyl, 4-hydroxy-1-piperidyl,morpholin-4-yl, substituted morpholinyl, such as 2,6-dimethylmorpholin-4-yl, piperazinyl, such as piperazin-1-yl, substitutedpiperazinyl, such as 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl,4-ethoxycarbonylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, ortetrahydropyranyl, such as tetrahydropyran-4-yl, and which canoptionally be condensated with aromatic rings, and which may optionallybe substituted, such as with 1 to 2 substituents such as hydroxy,halogen, C₁-C₆-alkyl, etc. The definition of the optionally substitutedalkyl groups thus includes also alkyl groups, which are substituted bythe above-defined heterocyclic groups, such as 3-(1-piperidyl)propyl,3-pyrrolidin-1-ylpropyl, 3-morpholinopropyl, 2-morpholinoethyl,2-tetrahydropyran-4-ylethyl, 3-tetrahydropyran-4-ylpropyl,3-(azetidin-1-yl) propyl etc.

Examples of a linear or branched alkyl group substituted with halogenand having 1 to 8, preferably 1 to 6 carbon atoms include, inparticular: a fluoromethyl group, a difluoromethyl group, atrifluoromethyl group, a chloromethyl group, a dichloromethyl group, atrichloromethyl group, a bromomethyl group, a dibromomethyl group, atribromomethyl group, a 1-fluoroethyl group, a 1-chloroethyl group, a1-bromoethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a2-bromoethyl group, a 1,2-difluoroethyl group, a 1,2-dichloroethylgroup, a 1,2-dibromoethyl group, a 2,2,2-trifluoroethyl group, aheptafluoroethyl group, a 1-fluoropropyl group, a 1-chloropropyl group,a 1-bromopropyl group, a 2-fluoropropyl group, a 2-chloropropyl group, a2-bromopropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a3-bromopropyl group, a 1,2-difluoropropyl group, a 1,2-dichloropropylgroup, a 1,2-dibromopropyl group, a 2,3-difluoropropyl group, a2,3-dichloropropyl group, a 2,3-dibromopropyl group, a3,3,3-trifluoropropyl group, a 2,2,3,3,3-pentafluoropropyl group, a2-fluorobutyl group, a 2-chlorobutyl group, a 2-bromobutyl group, a4-fluorobutyl group, a 4-chlorobutyl group, a 4-bromobutyl group, a4,4,4-trifluorobutyl group, a 2,2,3,3,4,4,4-heptafluorobutyl group, aperfluorobutyl group, a 2-fluoropentyl group, a 2-chloropentyl group, a2-bromopentyl group, a 5-fluoropentyl group, a 5-chloropentyl group, a5-bromopentyl group, a perfluoropentyl group, a 2-fluorohexyl group, a2-chlorohexyl group, a 2-bromohexyl group, a 6-fluorohexyl group, a6-chlorohexyl group, a 6-bromohexyl group, a perfluorohexyl group, a2-fluoroheptyl group, a 2-chloroheptyl group, a 2-bromoheptyl group, a7-fluoroheptyl group, a 7-chloroheptyl group, a 7-bromoheptyl group, aperfluoroheptyl group, etc.

Examples of an alkyl group substituted with hydroxy include theabove-mentioned alkyl residues, which have 1 to 3 hydroxy residues, suchas, for example hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl.

Optionally substituted aryl preferably includes according to theinvention aromatic hydrocarbon residues with 6 to 14 carbon atoms (withno hetero atom in the aromatic ring system), for example: phenyl,naphthyl, phenanthrenyl and anthracenyl. The aforementioned aromaticgroups may be unsubstituted or substituted. In case of substitution,they preferably have one or more, preferably one (1) or two (2)substituents, in particular halogen, hydroxy, alkyl, alkoxy, in eachcase as explained above or below. A preferred aromatic group is phenyl.A preferred alkyl substituted with an aromatic group (arylalkyl) isbenzyl.

Optionally substituted aryl according to the present invention furtherincludes optionally substituted heteroaryl, that is, heteroaromaticgroups, such as for example: pyridyl, pyridyl-N-oxide, pyrimidyl,pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl,benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl,naphthyridinyl, quinazolinyl. 5- or 6-membered aromatic heterocyclessuch as, for example pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl,furyl and thienyl are preferred. The aforementioned heteroaromaticgroups may be unsubstituted or substituted. In case of substitution,they preferably have one or more, preferably one (1) or two (2)substituents, in particular halogen, hydroxy, alkyl, alkoxy, in eachcase as explained above or below. Preferred examples of an alkylsubstituted with a heteroaromatic group (hetarylalkyl) are methyl,ethyl, or propyl, in each case substituted with a heteroaromatic group,such as thienylmethyl, pyridylmethyl etc.

Optionally substituted alkoxy (RO—) is formally derived from the abovementioned optionally substituted alkyl residues by adding an oxygen atomand includes in context with the present invention, for example, linearor branched alkoxy groups with up to 6 carbon atoms, such as a methoxygroup, an ethoxy group, an n-propyloxy group, an i-propyloxy group, ann-butyloxy group, an i-butyloxy group, a sec-butyloxy group, at-butyloxy group, an n-pentyloxy group, an i-pentyloxy group, asec-pentyloxy group, a t-pentyloxy group, a 2-methylbutoxy group, ann-hexyloxy group, an i-hexyloxy group, a t-hexyloxy group, asec-hexyloxy group, a 2-methylpentyloxy group, a 3-methylpentyloxygroup, a 1-ethylbutyloxy group, a 2-ethylbutyloxy group, a1,1-dimethylbutyloxy group, a 2,2-dimethylbutyloxy group, a3,3-dimethylbutyloxy group, a 1-ethyl-1-methylpropyloxy group, etc. Amethoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxygroup, an n-butyloxy group, an i-butyloxy group, a sec-butyloxy group, at-butyloxy group, etc., are preferred. The alkoxy groups may optionallybe substituted, such as with the above possible substituents for alkyl.

Methoxy, ethoxy, n-propoxy, n-butoxy, etc. are preferred alkoxy.

Optionally substituted alkoxycarbonyl (RO—CO—) groups are formallyderived from the above alkyl groups by adding a —O—C(O)— residue underformation of an optionally substituted alkyloxycarbonyl residue. In thatregard reference can be made to the definition of the above-describedalkyl groups. As an alternative optionally substituted alkoxycarbonyl(RO—CO—) groups are derived from the aforementioned alkoxy groups by theaddition of a carbonyl group. Preferred alkoxycarbonyl groups compriseup to 6 carbon atoms and include for example: methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl tert.-butoxycarbonyletc., which may all be substituted as the above defined alkyl groups.

Optionally substituted amino carbonyl according to the invention can beformally derived from optionally substituted amino by adding a carbonylresidue ((R)₂N—C(═O)—). Therein optionally substituted amino preferablyincludes according to the invention: amino (—NH₂), optionallysubstituted mono- or dialkylamino (RHN—, (R)₂N—) for which with regardto the definition of optionally substituted alkyl reference can be madeto the above definition. Furthermore included are optionally substitutedmono- or diarylamino groups or mixed optionally substitutedalkylarylamino groups, for which as regards the definition of optionallysubstituted alkyl or aryl reference can be made to the abovedefinitions. Such groups include, for example methylamino,Dimethylamino, ethylamino, hydroxyethylamino, such as2-hydroxyethlyamino, Diethylamino, phenylamino, methylphenylamino etc.

Optionally substituted amino further includes an optionally substitutedcyclic amino, such as optionally substituted 5 or 6-membered cyclicamino that may contain further hetero atoms such as N, O, S, preferably0. Examples of such cyclic amino groups include the above-mentionednitrogen-containing heterocyclic groups bonded through a nitrogen atom,such as piperidin-1-yl, 4-hydroxy-piperidin-1-yl,2-(methoxycarbonyl)pyrrolidin-1-yl, pyrrolidin-1-yl, Morpholin-4-yl etc.

Examples of optionally substituted aminocarbonyl include therefore:Carbamoyl (H₂NC(═O)—), optionally substituted mono- ordialkylaminocarbonyl (RHNC(═O), (R)₂NC(═O)—), wherein reference can bemade to the above definition of optionally substituted alkyl.Furthermore are included optionally substituted mono- ordiarylaminocarbonyl residues or mixed, optionally substitutedalkylarylaminocarbonyl residues, wherein reference can be made to theabove definitions of optionally substituted alkyl or aryl. Preferredsubstituted aminocarbonyl groups comprise up to 14 carbon atoms. Suchgroups include for example methylaminocarbonyl, dimethylaminocarbonyl,ethylaminocarbonyl, diethylaminocarbonyl, phenylaminocarbonyl,diphenylaminocarbonyl, methylphenylaminocarbonyl etc.

Examples of the aforementioned ring formation of the substituents R₂ andR₃ as represented schematically by the following formula:

(wherein R₁ can have the mentioned meanings)

Include in particular:

compounds in which R₂ and R₃ together preferably represent a propylene(—CH₂—CH₂—CH₂—)— or a butylene (—CH₂—CH₂—CH₂—CH₂—) group, in whichoptionally one methylene group (—CH₂—) respectively can be replaced with—O—, —NH— or —NR₄—, wherein R₄ is defined as mentioned above and whereinthe groups formed by R₂ and R₃ optionally can furthermore respectivelybe substituted by one to three substituents selected from the groupconsisting of hydroxy, oxo, C₁-C₄ alkoxy, amino and mono- ordi-(C₁-C₄-alkyl)amino.

Exemplary ligands are the following:

wherein R₁ respectively is as described above.

The iron(III) complex compounds of the formula (II) are particularlypreferred:

wherein R₁, R₂, and R₃ are each defined as above or preferably asdefined below.

Furthermore, preferably R₁, R₂ and R₃ are the same or different and areselected from:

-   -   hydrogen,    -   C₁₋₆-alkyl, preferably as presented above, halogen, preferably        as presented above,    -   C₃₋₆-cycloalkyl, preferably as presented above,    -   C₃₋₆-cycloalkyl-C₁₋₄-alkyl, preferably as presented above,    -   C₁₋₄-alkoxy-C₁₋₄-alkyl, preferably as presented above,    -   C₁₋₄-alkoxy-carbonyl, preferably as presented above,    -   C₁₋₄-mono-oder dialkylaminocarbonyl, preferably as presented        above,    -   aminocarbonyl or carbamoyl (H₂NCO—), respectively    -   hydroxy-C₁₋₄-alkyl, preferably as presented above, and    -   halogen-C₁₋₄-alkyl, preferably as presented above;

or

-   -   R₂ and R₃ together with the carbon atoms to which they are        bonded, form an optionally substituted saturated or unsaturated        5- or 6-membered ring, as explained above.

Particularly preferably R₁, R₂, and R₃ are the same or different and areselected from: hydrogen and C₁₋₆-alkyl, preferably as presented above,in particular hydrogen, methyl, ethyl and propyl, in particulari-propyl, butyl, especially sec-butyl. Most preferably, R₁, R₂ and R₃are selected from: hydrogen, methyl and ethyl.

It is also particularly preferred, that R₂ and R₃ together with thecarbon atoms to which they are bonded, form an optionally substitutedsaturated or unsaturated 5- or 6-membered ring, in particular anoptionally substituted saturated 5- or 6-membered ring, particularlypreferably a saturated 6-membered ring.

In a further embodiment of the invention there are provided the iron(III)-pyrazine-2-ol-1-oxide complex compounds in solid form. The term“solid form” means here in particular in contrast to the dissolved form,in which the iron (III)-pyrazine-2-ol-1-oxide complex compounds arepresent dissolved in a solvent such as water. The term “solid form”means also that the iron (III)-pyrazine-2-ol-1-oxide complex compoundsat room temperature (23° C.) are present in solid form. The iron(III)-pyrazine-2-ol-1-oxide complex compounds can be present in anamorphous, crystalline or partially crystalline form. Also, the iron(III)-pyrazine-2-ol-1-oxide complex compounds of the invention may existas hydrates.

It is clear to the person skilled in the art that the ligands accordingto the invention

arise from the corresponding pyrazine-2-ol-1-oxide compounds:

In the pyrazine-2-ol-1-oxide compounds there is a keto-enol-tautomerismbetween 1-hydroxypyrazine-2(1H) (IIIa) and pyrazine-2-ol-1-oxide (III),wherein the equilibrium state is determined by various factors.

The ligand is formally obtained by cleavage of a proton from thecorresponding pyrazine-1-oxide compounds (III):

so formally carries a single negative charge.

Furthermore it is clear to a person skilled in the art that thepyrazine-2-ol-1-oxide compounds as used according to the presentinvention can be drawn by different notations (a and b), but bothinclude the same issue of the N-oxide.

The same applies for the corresponding deprotonated form of thepyrazine-2-ol-1-oxide ligand compounds. Within the scope of the presentinvention all tautomeric forms are included, even if only one of themesomeric formulas is drawn.

Depending on the substituent R₁, R₂, and R₃ they can also participate inthe tautomeric resonance structures in the pyrazine-2-ol-1-oxide ligandand within the scope of the invention all such tautomers are included.

The iron(III) pyrazine-2-ol-oxide complex compounds of the presentinvention, in particular such as of the general formula (II) or thecorresponding pyrazine-2-ol-1-oxide ligands, respectively, can bepresent in the form of various isomers or tautomers. Isomeric formsinclude, for example, regioisomers which differ in the position of theligands relative to one another, including so-called optical isomersthat have an image/mirror image relationship to one another. Ifasymmetric carbon atoms are present, the ligands can be present in theform of optical isomers which have an image/mirror image relationship toone another, and include pure enantiomers, mixtures of the enantiomers,in particular racemates. Enantiomerically pure ligands can be obtained,as is known to the person skilled in the art, by optical dissolutionmethods, such as reaction with chiral reagents to form diastereomers,separation of the diastereomers and release of the enantiomers.

Further preferred embodiments of the invention include:

(In the present invention, the digits 1-6 in “1-6C” or “01-6” or “1-4”in “1-4C” or “01-4” etc. in each case signify the number of the carbonatoms of the subsequent hydrocarbon group designations).

R₁, R₂ and R₃ are selected from the group consisting of:

-   -   hydrogen,    -   1-6C-alkyl, (this means alkyl with 1 to 6 carbon atoms),    -   3-6C-cycloalkyl,    -   3-6C-cycloalkyl-1-4C-alkyl,    -   1-4C-alkoxy-1-4C-alkyl,    -   hydroxy-1-4C-alkyl,        or R₂ and R₃ together form a propylene (—CH₂—CH₂—CH₂), butylene        (—CH₂—CH₂—CH₂—CH₂—), azabutylene or oxabutylene group;        oder R₂ and R₃ bilden zusammen mit den Kohlenstoffen an die sie        gebunden sind, ein ungesättigten Ring, der gegebenenfalls ein        oder zwei weitere Heteroatome aufweisen kann, or        pharmaceutically acceptable salts thereof.

Preferably, the aforementioned substituent groups are defined asfollows:

1-6C-alkyl preferably includes straight-chained or branched alkyl groupswith 1 to 6 carbon atoms. Examples therefore can be methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyln-pentyl, iso-pentyl, neo-pentyl, n-hexyl, iso-hexyl and neo-hexyl.

3-6C-cycloalkyl preferably includes cycloalkyl 1 to 6 carbon atoms, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

3-6C-cycloalkyl-1-4C-alkyl preferably includes a 1-6C-alkyl groupdescribed above, substituted with a 3-6C-cycloalkyl group describedabove. Examples therefor can be a cyclopropylmethyl, cyclopentylmethyland cyclohexylmethyl group.

1-3C-alkoxy-carbonyl-1-6C-alkyl, preferably includes a 1-6C-alkyl groupdescribed above, which is linked to a carbonyl group which is presentwith a 1-3C alkoxy group as a carboxylic acid ester. Examples thereforcan be methoxycarbonylmethyl, ethoxycarbonylmethyl,methoxycarbonylethyl, ethoxycarbonylethyl and isopropoxycarbonylmethyl.

1-4C-alkoxy preferably includes a 1-4C-alkoxy group, in which an oxygenatom is connected to a straight or branched alkyl chain with 1-4 carbonatoms. Examples of this group can be methoxy, ethoxy, propoxy andisobutoxy.

1-4C-alkoxy-1-4C-alkyl preferably includes a 1-4C-alkoxy group describedabove, which is substituted with a 1-4C-alkyl group described above.Examples of this group can be methoxyethyl, ethoxypropyl, methoxypropyl,isobutoxymethyl.

Hydroxy-1-4C-alkyl includes a 1-4C-alkyl group described above, which issubstituted with a hydroxy group. Examples therefor can be hydroxyethyl,hydroxybutyl and hydroxyisopropyl.

Particularly preferred are:

R₁ R₂ and R₃ are selected from the group consisting of:

-   -   hydrogen,    -   1-6C-alkyl,    -   1-4C-alkoxy-1-4C-alkyl,    -   hydroxy-1-4C-alkyl;        or R₂ and R₃ together form a propylene (—CH₂—CH₂—CH₂), butylene        (—CH₂—CH₂—CH₂—CH₂—), azabutylene or oxabutylene group;        or R₂ and R₃ together with the carbon atoms to which they are        bonded form an unsaturated ring, which may contain further        heteroatoms.

Particularly preferably:

R₁, R₂ and R₃ are selected from the group consisting of:

-   -   hydrogen    -   1-6C-alkyl;    -   1-4C-alkoxy-1-4C-alkyl        or R₂ and R₃ together form a propylene (—CH₂—CH₂—CH₂) or        butylene (—CH₂—CH₂—CH₂—CH₂—) group;        or R₂ and R₃ together with the carbona atoms to which they are        bonded form an unsaturated ring, which may contain one further        nitrogen atom.

Particularly preferred complex compounds of the general formula (II) aredescribed in the examples.

The invention further relates to a method for the preparation of theiron(III) complex compounds according to the invention which comprisesthe reaction of a pyrazine-2-ol-1-oxide of formula (III) with aniron(III) salt.

Pyrazine-2-ol-1-oxides as the starting compounds include in particularthose of the formula (III):

wherein R₁, R₂ and R₃ are defined as above, to the tautomeric resonancestructures of which it has been referred to.

Examples of suitable iron(III) salts include: iron(III) chloride,iron(III) acetate, iron(III) sulfate, iron(III) nitrate and iron(III)acetylacetonate, among which iron(III) chloride is preferred.

A preferred method is shown in the following scheme:

wherein R₁, R₂ and R₃ are as defined above, X is an anion such ashalogenide, such as chloride, a carboxylate, such as acetate, sulphate,nitrate and acetylacetonate and base is a common organic or inorganicbase.

In the method according to the invention, preferably 3 eqpyrazine-2-ol-1-oxide (III), using suitable iron(III) salts (IV) (inthis case Fe(III) chloride, Fe(III) acetate, Fe(III) sulphate andFe(III) acetylacetonate are particularly suitable), are reacted understandard conditions to form the corresponding complexes of the generalformula (II). In this case, the synthesis is carried out under the pHconditions optimal for complex formation. The optimum pH value is set byadding a base (V); in this case, the use of sodium hydroxide, sodiumcarbonate, sodium hydrogen carbonate, sodium methanolate, potassiumhydroxide, potassium carbonate, potassium hydrogen carbonate orpotassium methanolate is particularly suitable.

The ligands (III) required for the preparation of the complexes whereprepared according to the following synthesis method (J. Chem. Soc.1949, 2707-2712). For this purpose, the commercially available orsynthesized 2-aminohydroxamic acids (IV) were reacted under standardconditions with the commercially available or synthesized 1-2-dicarbonylcompounds of the general formula (V) to form ligands of the generalformula (III). When using unsymmetrical 1-2-dicarbonyl compounds in thissynthesis, this can result in the occurrence of the correspondingregioisomers (IIIa), which can be separated by standard methods whichare well known to a person skilled in the art. For other substitutionpatterns of diketone (V) the reaction can also proceed largelyregioselective, such as e.g. in the case of R₂=methyl, R₃=hydrogen.

Analogously, it is also possible to use slightly modified synthesisroutes under reactions conditions which are well know to a personskilled in the art, for the preparation of the respective ligands of thegeneral formula (III). I. e., in the synthesis of Ohkanda et al. (Bull.Chem. Soc. Jpn. 1993, 66, 841-847) starting from the N-terminalprotected amino acid of the general formula (VI) the correspondingO-benzyl protected amino hydroxamic acid (VII) can be prepared, whichcan be reacted to form the ligands of the general formula (III) afterreaction with 1-2-dicarbonyl compounds of the general formula (IV) andcleavage of the O-benzyl group. In this alternative synthesis route itcan come to the occurrence of (IIIa), too.

In general, the preparation of the pyrazine-2-ol-oxides (III) can be aswell carried out by other synthesis routes familiar to a skilled person.Thus, for example, there is the possibility to react the respectivesubstituted pyrazines (VIII) with suitable oxidizing agents, such ashydrogen peroxide or peroxycarboxylic acids, to form the desiredproducts of general formula (III) (e.g. J. Org. Chem. 1958, 23,1603-1606), wherein the region chemistry of the oxidation as well as theoxidation degree (simple or double) is determined by the reactionconditions, particularly the oxidizing agent and the substitutionpattern of the corresponding pyrazines (e.g. J. Heterocycl. Chem. 1983,19, 1061, J. Heterocycl. Chem. 1989, 26, 812).

Examples of the pyrazine-2-ol-1-oxide starting compounds (III) includeparticularly the following:

From these compounds the ligands of the iron complex compounds accordingto the present invention are derived by simple deprotonation at thehydroxy group.

Pharmaceutically acceptable salts of the compounds according to theinvention in which the iron(III) complex formally carries a positivecharge include, for example, salts with suitable anions, such ascarboxylates, sulfonates, sulfates, chlorides, bromides, iodides,phosphates, tartrates, methane sulfonates, hydroxyethane sulfonates,glycinates, maleates, propionates, fumarates, toluene sulfonates,benzene sulfonates, trifluoroacetates, naphthalenedisulfonates-1,5,salicylates, benzoates, lactates, salts of malic acid, salts of3-hydroxy-2-naphthoic acid-2, citrates and acetates.

Pharmaceutically acceptable salts of the compounds according to theinvention in which the iron(III) complex formally carries a negativecharge include, for example, salts with suitable pharmaceuticallyacceptable bases, such as, for example, salts with alkaline oralkaline-earth hydroxides, such as NaOH, KOH, Ca(OH)₂, Mg(OH)₂ etc.,amine compounds such as ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine,methylglucamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine,N-methylpiperidin, 2-amino-2-methyl-propanol-(1),2-amino-2-methyl-propandiol-(1,3),2-amino-2-hydroxyl-methyl-propandiol-(1,3) (TRIS) etc.

The water-solubility or the solubility in physiological saline solutionand thus, optionally, also the efficacy of the compounds according tothe invention can be significantly influenced by salt formation ingeneral, specifically by the choice of the counterion.

Preferably, the compounds according to the invention constitute neutralcomplex compounds.

Advantageous Pharmacological Effects:

Surprisingly, the inventors found that the iron(III)pyrazine-2-ol-1-oxide complex compounds which are the subject matter ofthe present invention and which are represented, in particular, by thegeneral structural formula (II), are stable bioavailable iron complexesand suitable for use as a medicament for the treatment and prophylaxisof iron deficiency symptoms and iron deficiency anemias as well as thesymptoms accompanying them.

The medicaments containing the compounds according to the invention aresuitable for use in human and veterinary medicine.

The compounds according to the invention are thus also suitable forpreparing a medicament for the treatment of patients suffering fromsymptoms of an iron deficiency anemia, such as, for example: fatigue,listlessness, lack of concentration, low cognitive efficiency,difficulties in finding the right words, forgetfulness, unnaturalpallor, irritability, acceleration of heart rate (tachycardia), sore orswollen tongue, enlarged spleen, desire for strange foods (pica),headaches, lack of appetite, increased susceptibility to infections ordepressive moods.

The iron(III) complex compounds according to the invention arefurthermore suitable for the treatment of iron deficiency anemia inpregnant women, latent iron deficiency anemia in children andadolescents, iron deficiency anemia caused by gastrointestinalabnormalities, iron deficiency anemia due to blood loss, such asgastrointestinal hemorrhage (e.g. due to ulcers, carcinoma, hemorrhoids,inflammatory disorders, taking of acetylsalicylic acid), iron deficiencyanemia caused by menstruation, iron deficiency anemia caused byinjuries, iron deficiency anemia due to sprue, iron deficiency anemiadue to reduced dietary iron uptake, in particular in selectively eatingchildren and adolescents, immunodeficiency caused by iron deficiencyanemia, brain function impairment caused by iron deficiency anemias,restless leg syndrome caused by iron deficiency anemias, iron deficiencyanemias in the case of cancer, iron deficiency anemias caused bychemotherapies, iron deficiency anemias triggered by inflammation (Al),iron deficiency anemias in the case of congestive cardiac insufficiency(CHF; congestive heart failure), iron deficiency anemias in the case ofchronic renal insufficiency stage 3-5 (CKD 3-5; chronic kidney diseasesstage 3-5), iron deficiency anemias triggered by chronic inflammation(ACD), iron deficiency anemias in the case of rheumatoid arthritis (RA),iron deficiency anemias in the case of systemic lupus erythematosus(SLE) and iron deficiency anemias in the case of inflammatory boweldiseases (IBD).

Administration can take place over a period of several months until theiron status is improved, which is reflected, for example, by thehemoglobin level, transferrin saturation and the serum ferritin level ofthe patients, or until the desired improvement of the state of healthaffected by iron deficiency anemia. The preparation according to theinvention can be taken by children, adolescents and adults.

The applied compounds according to the invention can in this case beadministered both orally as well as parentally. Oral administration ispreferred.

The compounds according to the invention and the aforementionedcombinations of the compounds according to the invention with otheractive substances or medicines can thus be used, in particular, for thepreparation of medicaments for the treatment of iron deficiency anemia,such as iron deficiency anemia in pregnant women, latent iron deficiencyanemia in children and adolescents, iron deficiency anemia caused bygastrointestinal abnormalities, iron deficiency anemia due to bloodloss, such as gastrointestinal hemorrhage (e.g. due to ulcers,carcinoma, hemorrhoids, inflammatory disorders, taking ofacetylsalicylic acid), menstruation, injuries, iron deficiency anemiadue to sprue, iron deficiency anemia due to reduced dietary iron uptake,in particular in selectively eating children and adolescents,immunodeficiency caused by iron deficiency anemia, brain functionimpairment caused by iron deficiency anemia, restless leg syndrome.

The application according to the invention leads to an improvement ofthe iron, hemoglobin, ferritin and transferrin levels, which, inparticular in children and adolescents, but also in adults, isaccompanied by an improvement in short-term memory tests (STM),long-term memory tests (LTM), Ravens' progressive matrices test, in theWechsler adult intelligence scale (WAIS) and/or in the emotionalcoefficient (Baron EQ-i, YV test, youth version), or to an improvementof the neutrophile level, the antibody levels and/or lymphocytefunction.

Furthermore, the present invention relates to pharmaceuticalcompositions comprising one or more of the compounds according to theinvention, in particular according to the formula (II), as well asoptionally one or more further pharmaceutically effective compounds, aswell as optionally one or more pharmacologically acceptable carriersand/or auxiliary substances and/or solvents. The said pharmaceuticalcompositions contain, for example up to 99 weight-% or up to 90 weight-%or up to 80 weight-% or or up to 70 weight-% of the compounds of theinvention, the remainder being each formed by pharmacologicallyacceptable carriers and/or auxiliaries and/or solvents.

These are common pharmaceutical carriers, auxiliary substances orsolvents. The above-mentioned pharmaceutical compositions are suitable,for example, for intravenous, intraperitoneal, intramuscular,intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous,oral, rectal, transdermal, topical, intradermal, intragasteral orintracutaneous application and are provided, for example, in the form ofpills, tablets, enteric-coated tablets, film tablets, layer tablets,sustained release formulations for oral, subcutaneous or cutaneousadministration (in particular as a plaster), depot formulations,dragees, suppositories, gels, salves, syrup, granulates, suppositories,emulsions, dispersions, microcapsules, microformulations,nanoformulations, liposomal formulations, capsules, enteric-coatedcapsules, powders, inhalation powders, microcrystalline formulations,inhalation sprays, epipastics, drops, nose drops, nose sprays, aerosols,ampoules, solutions, juices, suspensions, infusion solutions orinjection solutions etc.

Preferably, the compounds according to the invention as well aspharmaceutical compositions containing such compounds are appliedorally, although other forms, such as parentally, in particularintravenously, are also possible.

For this purpose, the compounds according to the invention arepreferably provided in pharmaceutical compositions in the form of pills,tablets, enteric-coated tablets, film tablets, layer tablets, sustainedrelease formulations for oral administration, depot formulations,dragees, granulates, emulsions, dispersions, microcapsules,microformulations, nanoformulations, liposomal formulations, capsules,enteric-coated capsules, powders, microcrystalline formulations,epipastics, drops, ampoules, solutions, suspensions, infusion solutionsor injection solutions.

In a preferred embodiment of the invention the iron complex compoundsare administered in the form of a tablet or capsule. These can forexample be present as acid-resistant forms or with pH-dependentcoatings.

The compounds according to the invention can be administered inpharmaceutical compositions which may contain various organic orinorganic carrier and/or auxiliary materials as they are customarilyused for pharmaceutical purposes, in particular for solid medicamentformulations, such as, for example, excipients (such as saccharose,starch, mannitol, sorbitol, lactose, glucose, cellulose, talcum, calciumphosphate, calcium carbonate), binding agents (such as cellulose,methylcellulose, hydroxypropylcellulose, polypropyl pyrrolidone,gelatine, gum arabic, polyethylene glycol, saccharose, starch),disintegrating agents (such as starch, hydrolyzed starch,carboxymethylcellulose, calcium salt of carboxymethylcellulose,hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, calciumphosphate, calcium citrate), lubricants (such as magnesium stearate,talcum, sodium laurylsulfate), a flavorant (such as citric acid,menthol, glycin, orange powder), preserving agents (such as sodiumbenzoate, sodium bisulfite, methylparaben, proylparaben), stabilizers(such as citric acid, sodium citrate, acetic acid and multicarboxylicacids from the titriplex series, such as, for example,diethylenetriaminepentaacetic acid (DTPA), suspending agents (such asmethycellulose, polyvinyl pyrrolidone, aluminum stearate), dispersingagents, diluting agents (such as water, organic solvents), beeswax,cocoa butter, polyethylene glycol, white petrolatum, etc.

Liquid medicament formulations, such as solvents, suspensions and gelsusually contain a liquid carrier, such as water and/or pharmaceuticallyacceptable organic solvents. Furthermore, such liquid formulations canalso contain pH-adjusting agents, emulsifiers or dispersing agents,buffering agents, preserving agents, wetting agents, gelatinizing agents(for example methylcellulose), dyes and/or flavouring agents. Thecompositions may be isotonic, that is, they can have the same osmoticpressure as blood. The isotonicity of the composition can be adjusted byusing sodium chloride and other pharmaceutically acceptable agents, suchas, for example, dextrose, maltose, boric acid, sodium tartrate,propylene glycol and other inorganic or organic soluble substances. Theviscosity of the liquid compositions can be adjusted by means of apharmaceutically acceptable thickening agent, such as methylcellulose.Other suitable thickening agents include, for example, xanthan gum,carboxymethylcellulose, hydroxypropylcellulose, carbomer and the like.The preferred concentration of the thickening agent will depend on theagent selected. Pharmaceutically acceptable preserving agents can beused in order to increase the storage life of the liquid composition.Benzyl alcohol can be suitable, even though a plurality of preservingagents including, for example, paraben, thimerosal, chlorobutanol andbenzalkonium chloride can also be used.

The active substance can be administered, for example, with a unit doseof 0.001 mg/kg to 500 mg/kg body weight, for example 1 to 4 times a day.However, the dose can be increased or reduced depending on the age,weight, condition of the patient, severity of the disease or type ofadministration.

EXAMPLES

The designation of the ligands has been carried according to the IUPACnomenclature with the program ACD/name, version 12.01 according toAdvanced Chemistry Development Inc.

Abbreviations s singlet t triplet d doublet q quartet dd double doubletm multiplet (broad/superimposed) L ligand

Starting Compounds:

A. Pyrazine-2-ol 1-oxide

The synthesis has been carried out in analogy to the followingliterature: G. Dunn et al., J. Chem. Soc. 1949, 2707-2712.

B. 5,6-Dimethyl-pyrazine-2-ol 1-oxide

The synthesis has been carried out in analogy to the followingliterature: G. Dunn et al., J. Chem. Soc. 1949, 2707-2712.

C. 3-Methylpyrazine-2-ol-1-oxide

The synthesis has been carried out in analogy to the followingliterature: G. Dunn et al., J. Chem. Soc. 1949, 2707-2712.

D. 3,5,6-Trimethylpyrazine-2-ol-1-oxide

The synthesis has been carried out in analogy to the followingliterature: G. Dunn et al., J. Chem. Soc. 1949, 2707-2712.

E. 5-Methylpyrazine-2-ol-1-oxide

100 mmol (9 g) glycine hydroxamic acid were cooled to −25° C. in 200 mlwater and methanol each, 100 mmol (15.4 ml 40% solution) methylglyoxalwere added dropwise and subsequently the pH was adjusted toapproximately pH 11 with 10 ml 30% NaOH. Heating up to 5° C. was carriedout in 2 h and concentrated under vacuum to half of the solvent volume.A pH 3 was adjusted with 20% HCl, precipitated solid was filtered offand dried. 7.28 g (52% yield) of the title compound were obtained.

IR (in substance, cm⁻¹): 1644, 1577, 1527, 1454, 1425, 1381, 1333, 1229,1141, 1062, 1028, 949, 896, 835, 806, 732. CHN-elementary analysis: C,42.91; H, 4.49; N, 19.54. 1 H-NMR (DMSO-d₆, 400 MHz): δ [ppm]=8.04 (s,1H), 7.83 (s, 1H), 2.21 (s, 3H).

F. 3,5-Dimethylpyrazine-2-ol-1-oxide

407 mmol (42.4 g) alanine hydroxamic acid were cooled to −10° C. in 200ml water and methanol each, 400 mmol (57 ml 40% solution) methylglyoxalwere added dropwise and subsequently the pH was adjusted toapproximately pH 11 with 19 ml 30% NaOH. Heating up to 0° C. was carriedout within 2 h and then pH 3 was adjusted with 20% NaOH. The solutionwas concentrated until dryness under vacuum distillation, the residuewas heated to reflux with 50 ml ethanol, after cooling filtering wascarried out and the filtrate again concentrated until dryness. 44 g ofthe solid residue were dissolved in 50 ml water and 15 mmol (4.06 g)FeCl₃*6H₂O were added, heated up to 50° C. for 30 minutes, concentratedand stored at 5° C. for 4 h. The precipitated solid was filtered off anddried. 3.7 g solid in 50 ml water and 10 ml ethanol were adjusted to pH11 with 6 ml 1 M NaOH, stirred over night and centrifugalized. Thesupernatant was decanted, pH 3 was adjusted with 3 ml 1 M HCl andconcentrated until dryness. 4.2 g solid were refluxed in 20 ml ethanol,cooled and filtered off. The filtrate was again concentrated untildryness and the obtained 2.8 g solid were suspended with 10 ml water,heated up to 50° C. and left for cooling over night. The suspension wascentrifugalized, the supernatant decanted and concentrated untildryness. 2.0 g (3.5% yield) of the title compound were obtained.

IR (in substance, cm⁻¹): 1633, 1579, 1526, 1423, 1372, 1318, 1274, 1212,1148, 1030, 987, 934, 829, 751, 681, 613. LC-MS (m/z): 141.6 (M+H).CHN-elementary analysis: C, 50.15; H, 5.75; N, 18.83. 1 H-NMR (DMSO-d₆,400 MHz): δ [ppm]=7.64 (s, 1H), 2.31 (s, 3H), 2.15 (s, 3H).

G. 5,6-Diethylpyrazine-2-ol-1-oxide

The synthesis has been carried out in analogy to the followingliterature: G. Dunn et al., J. Chem. Soc. 1949, 2707-2712.

H. 5,6,7,8-Tetrahydroquinoxaline-2-ol-1-oxide

The synthesis has been carried out in analogy to the followingliterature: G. Dunn et al., J. Chem. Soc. 1949, 2707-2712.

I. 6-Methylpyrazine-2-ol-1-oxide

156 mmol (20 g) 2-chloro-6-methylpyrazine were dissolved in 80 ml 96%sulfuric acid, 222 mmol (63 g) potassium peroxodisulfate were addedportion wise at 10° C. and stirring was carried out for 2 days at 10° C.and 1 day at room temperature (see also C. E. Mixan, R. Garth, J. Org.Chem. 1977, 42, 1869-1871). The reaction mixture was poured on 200 gice, under addition of ethanol neutralization was carried out withcalcium hydroxide, then filtered off and washed with ethanol. Thefiltrate was evaporated until dryness, the obtained solid (20 g) wererefluxed in 300 ml 20% KOH solution for 3 h and after cooling pH 3 wasadjusted with 20% HCl. The solution was evaporated until dryness, theresidue boiled with 0.2 l ethanol under reflux for 2 h, after coolingfiltered and the filtrate evaporated until dryness. Afterrecrystallization from ethanol/tetrahydrofuran from 7.4 g raw product2.17 g (10% yield, 93% purity) of the title compound were obtained.

IR (in substance, cm⁻¹): 1649, 1573, 1541, 1454, 1413, 1389, 1374, 1297,1247, 1208, 1171, 1126, 1055, 1037, 981, 896, 848, 816, 718. LC-MS(m/z): 127.4 (M+H). CHN-elementary analysis: C, 44.77; H, 4.56; N,20.72. 1 H-NMR (DMSO-d₆, 400 MHz): δ [ppm]=7.95 (s, 1H), 7.30 (s, 1H),2.31 (s, 3H).

J. 3,6-Dimethylpyrazine-2-ol-1-oxide

The synthesis has been carried out in analogy to the followingliterature: A. Ohta et al., J. Heterocyclic Chem. 1981, 18, 555-558.

Iron Complex Compounds Examples Example 1 Tris-(pyrazine-2-ol1-oxide)iron(III)-complex

15 mmol (1.77 g) pyrazine-2-ol-1-oxide (in analogy to G. Dunn et al., J.Chem. Soc. 1949, 2707-2712) were dissolved in 50 ml ethanol, heated toreflux and 5 mmol (1.352 g) FeCl₃*6H₂O dissolved in 20 ml ethanol wereadded. Under reflux 50 ml water were added dropwise and the reactionmixture was left for cooling. Subsequently pH 4.5 was adjusted with 15ml 1 M NaOH, stirred at 50° C. for 2 h and after cooling the product wasfiltered off and dried in a vacuum drying oven at 50° C. 1.89 g (95%Fe-yield) of the title compound were obtained.

IR (in substance, cm⁻¹): 3096, 3060, 1595, 1517, 1476, 1440, 1340, 1289,1188, 1157, 1048, 921, 890, 830, 801. Fe-content: 13.8% [m/m]chloride-content: 3.0% [m/m]

Example 2

Tris-(5,6-dimethyl pyrazine-2-ol 1-oxide)iron(III)-complex

15 mmol (2.213 g) 5,6-dimethylpyrazine-2-ol 1-oxide (in analogy to G.Dunn et al., J. Chem. Soc. 1949, 2707-2712) were dissolved in 50 mlethanol, heated to reflux and 5 mmol (1.352 g) FeCl₃*6H₂O dissolved in25 ml ethanol were added. Under reflux 75 ml water were added dropwiseand the reaction mixture was left for cooling. Subsequently pH 4.5 wasadjusted with 10 ml 1 M NaOH, stirred at 50° C. for 2 h and aftercooling the product was filtered off and dried in a vacuum drying ovenat 50° C. 2.07 g (86% Fe-yield) of the title compound were obtained.

IR (in substance, cm⁻¹): 3037, 1594, 1477, 1361, 1276, 1217, 1161, 1093,1065, 1018, 968, 878, 771, 692. Fe-content: 11.63% [m/m]chloride-content: 0.0% [m/m] (not detectable)

Example 3 Tris-(3-methylpyrazine-2-ol-1-oxide)iron(III)-complex

12 mmol (1.51 g) 3-methylpyrazine-2-ol-1-oxide (in analogy to G. Dunn etal., J. Chem. Soc. 1949, 2707-2712) were heated to reflux in 100 mlethanol and 4 mmol (1.08 g) FeCl₃*6H₂O dissolved in 20 ml ethanol wereadded. Under reflux 120 ml water were added dropwise, half of thesolvent were distilled off and the reaction mixture was left forcooling. Subsequently pH was adjusted to 4.4 with 9 ml 1 M NaOH andstirred for 15 min at 50° C. After cooling the product was filtered offand dried. 1.57 g (89% Fe-yield) of the title compound were obtained.

IR (in substance, cm⁻¹): 1588, 1523, 1487, 1373, 1333, 1314, 1257, 1185,1099, 1032, 946, 881, 809, 793, 752, 729. CHN-elementary analysis: C,41.92; H, 3.58; N, 19.33. Fe-content: 12.7% [m/m] chloride-content: 0.0%[m/m] (not detectable)

Example 4 Tris-(3,5,6-trimethylpyrazine-2-ol-1-oxide)iron(III)-complex

39 mmol (6.0 g) 3,5,6-trimethylpyrazine-2-ol-1-oxide (in analogy to G.Dunn et al., J. Chem. Soc. 1949, 2707-2712) were heated to reflux in 80ml ethanol and 13 mmol (3.5 g) FeCl₃*6H₂O dissolved in 10 ml ethanolwere added. Under reflux 80 ml water were added dropwise, half of thesolvent was distilled off and the reaction mixture was left for cooling.Subsequently pH 4.4 was adjusted with 48 ml 1 M NaOH and stirred for 15min at 50° C. After cooling the product was filtered off and dried. 6.48g (90% Fe-yield) of the title compound were obtained.

IR (in substance, cm⁻¹): 1587, 1486, 1413, 1363, 1332, 1182, 1129, 1082,1005, 940, 873, 749, 721. CHN-elementary analysis: C, 47.67; H, 5.26; N,15.82. Fe-content: 10.07% [m/m] chloride-content: 0.0% [m/m] (notdetectable)

Example 5 Tris-(5-methylpyrazine-2-ol-1-oxide)iron(III)-complex

42.8 mmol (6.0 g, 90% purity) 5-methylpyrazine-2-ol-1-oxide were heatedto reflux in 360 ml ethanol and 14.3 mmol (3.86 g) FeCl₃*6H₂O dissolvedin 20 ml ethanol were added. Under reflux 380 ml water were addeddropwise, half of the solvent was distilled off and the reaction mixturewas left for cooling. Subsequently pH 4.4 was adjusted with 45 ml 1 MNaOH and stirred for 30 min at 50° C. After cooling the product wasfiltered off and dried. 5.31 g (80% Fe-yield) of the title compound wereobtained.

IR (in substance, cm⁻¹): 1611, 1514, 1486, 1450, 1398, 1380, 1340, 1256,1205, 1184, 1122, 1039, 1007, 939, 918, 873, 840, 757, 742.CHN-elementary analysis: C, 40.88; H, 3.55; N, 18.86. Fe-content: 11.96%[m/m] chloride-content: 0% [m/m] (not detectable)

Example 6 Tris-(3,5-dimethylpyrazine-2-ol-1-oxide)-iron(III)-complex

11.4 mmol (1.68 g) 3,5-dimethylpyrazine-2-ol-1-oxide were heated toreflux in 50 ml ethanol and 3.8 mmol (1.03 g) FeCl₃*6H₂O dissolved in 10ml ethanol were added, under reflux 50 ml water were added dropwise,half of the solvent was distilled off and the reaction mixture was leftfor cooling. Subsequently pH 4.4 was adjusted with 7 ml 1 M NaOH andafter distillation of further 30 ml solvent stirred over night. Theproduct was filtered off and dried, 1.11 g (47% Fe-yield) of the titlecompound were obtained.

IR (in substance, cm⁻¹): 1526, 1489, 1373, 1332, 1306, 1226, 1141, 1055,940, 834, 748, 643, 605. Fe-content: 9.07% [m/m] chloride-content: 0.79%[m/m]

Example 7 Tris-(5,6-diethylpyrazine-2-ol-1-oxide)iron(III)-complex

6.6 mmol (1.1 g) 5,6-diethylpyrazine-2-ol-1-oxide were heated to refluxin 30 ml ethanol and 2.2 mmol (0.6 g) FeCl₃*6H₂O dissolved in 10 mlethanol were added. Under reflux 35 ml water were added dropwise, halfof the solvent was distilled off and the reaction mixture was left forcooling. Subsequently pH 4.2 was adjusted with 3.8 ml 1 M NaOH, theproduct was filtered off and dried. 1.15 g (99% Fe-yield) of the titlecompound were obtained.

IR (in substance, cm⁻¹): 2974, 2937, 2876, 1706, 1588, 1509, 1479, 1457,1353, 1260, 1214, 1158, 1105, 1048, 981, 950, 895, 782, 754, 687, 667,608. CHN-elementary analysis: C, 51.5; H, 6.27; N, 14.31. Fe-content:10.6% [m/m] chloride-content: 3.4% [m/m]

Example 8Tris-(5,6,7,8-tetrahydroquinoxaline-2-ol-1-oxide)-iron(III)-complex

15 mmol (2.62 g) 5,6,7,8-tetrahydroquinoxaline-2-ol-1-oxide were heatedto reflux in 100 ml ethanol and 5 mmol (1.35 g) FeCl₃*6H₂O dissolved in30 ml ethanol were added. Under reflux 100 ml water were added dropwise,half of the solvent was distilled off and the reaction mixture was leftfor cooling. Subsequently pH 4.5 was adjusted with 15 ml 1 M NaOH, theproduct was filtered off and dried. 2.52 g (91% Fe-yield) of the titlecompound were obtained.

IR (in substance, cm⁻¹): 2933, 1592, 1519, 1486, 1433, 1366, 1325, 1266,1245, 1217, 1184, 1134, 1102, 1067, 987, 966, 887, 856, 821, 762, 690,633, 611. CHN-elementary analysis: C, 52.44; H, 5.03; N, 15.21.Fe-content: 10.12% [m/m] chloride-content: 0.0% [m/m] (not detectable)

Example 9 Tris-(6-methylpyrazine-2-ol-1-oxide)iron(III)-complex

15.4 mmol (1.94 g) 6-methylpyrazine-2-ol-1-oxide were heated to refluxin 30 ml ethanol and 5.1 mmol (1.39 g) FeCl₃*6H₂O dissolved in 5 mlethanol were added. Under reflux further 45 ml ethanol and 75 ml waterwere added dropwise, 120 ml solvent were distilled off and the reactionmixture was left for cooling. Subsequently pH 4.4 was adjusted with 15ml 1 M NaOH, stirred for 30 min at 50° C., then the product was filteredoff and dried. 2.1 g (92% Fe-yield) of the title compound were obtained.

IR (in substance, cm⁻¹): 1597, 1528, 1478, 1409, 1379, 1357, 1218, 1189,1170, 1134, 1080, 1035, 989, 924, 861, 828, 712. CHN-elementaryanalysis: C, 40.68; H, 3.48; N, 18.77. Fe-content: 12.62% [m/m]chloride-content: 0.0% [m/m] (not detectable)

Example 10 Tris-(3,6-dimethylpyrazine-2-ol-1-oxide)-iron(III)-complex

15 mmol (2.1 g) 3,6-dimethylpyrazine-2-ol-1-oxide were heated to refluxin 50 ml ethanol and 5 mmol (1.35 g) FeCl₃*6H₂O dissolved in 10 mlethanol were added. Under reflux 50 ml water were added dropwise, 90 mlsolvent were distilled off and the reaction mixture was left forcooling. Subsequently pH 4.4 was adjusted with 12 ml 1 M NaOH, theproduct was filtered off and dried. 2.2 g (87% Fe-yield) of the titlecompound were obtained.

IR (in substance, cm⁻¹): 1599, 1529, 1486, 1455, 1413, 1370, 1316, 1252,1171, 1123, 1028, 978, 940, 859, 752, 707. CHN-elementary analysis: C,45.28; H, 4.31; N, 17.33. Fe-content: 11.04% [m/m] chloride-content:0.0% [m/m] (not detectable)

Pharmacological Testing Method:

The excellent Fe utilizations that can be accomplished through the Fecomplexes according to the invention were measured by means of thefollowing mouse model.

Male NMRI (SPF) mice (approximately 3 weeks old) were fed a low-irondiet (approx. 5 ppm iron) for approximately 3 weeks. The iron complexeswere then administered to them by means of a stomach tube (2 mg iron/kgbody weight/day) for 2 times 5 days, with an interruption of 2 days(days 1-5 and 8-12). 6 mice were the control group (negative control)and were administered with water instead. Utilization on day 15 wascalculated from the hemoglobin increase and the body weight increase inaccordance with the formula

${{Utilization}\mspace{14mu} (\%)} = {\frac{\Delta \; {iron}\mspace{14mu} {utilization}*100}{{Fe}\mspace{14mu} {{Dos}.}} = {\frac{\left( {{Fe}\mspace{14mu} {{ut}.{- {Fe}}}\mspace{14mu} {{ut}.\mspace{11mu} {Control}}} \right)*100}{{Fe}\mspace{14mu} {{Dos}.}} = {\quad{{{\left\lbrack {{{\left( {{{Hb}_{2{(3)}} \cdot {BW}_{9{(14)}}} - {{Hb}_{1} \cdot {BW}_{4}}} \right) \cdot 0},{07 \cdot 0},0034} - {\left( {{{Hb}_{2{(3)}\; {Control}} \cdot {BW}_{9{(14)}\; {Control}}} - {{Hb}_{1\; {Control}} \cdot {BW}_{4\; {Control}}}} \right) \cdot \left. \quad{0,{07 \cdot 0},0034} \right)}} \right\rbrack \cdot 100}\text{/}{Fe}\mspace{14mu} {{Dos}.}} = {\quad\left\lbrack {{{{{\left( {{{Hb}_{2{(3)}} \cdot {BW}_{9{(14)}}} - {{Hb}_{1} \cdot {BW}_{4}}} \right) \cdot 0},000238} - {{\left( {{{Hb}_{2{(3)}\; {Control}} \cdot {BW}_{9{(14)}\; {Control}}} - {{Hb}_{1\; {Control}} \cdot {BW}_{4\; {Control}}}} \right) \cdot \left. \quad{0,000238} \right\rbrack \cdot 100}\text{/}{Fe}\mspace{14mu} {{Dos}.}}} = {{{\left( {{{Hb}_{2{(3)}} \cdot {BW}_{9{(14)}}} - {{Hb}_{1} \cdot {BW}_{4}} - {{Hb}_{2{(3)}\; {Control}} \cdot {BW}_{9{(14)}\; {Control}}} + {{Hb}_{1\; {Control}} \cdot {BW}_{4\; {Control}}}} \right) \cdot 0},0238\text{/}{Fe}\mspace{14mu} {{Dos}.0.07}} = {{{Factor}\mspace{14mu} {for}\mspace{14mu} 70\mspace{14mu} {ml}\mspace{14mu} {blood}\mspace{14mu} {per}\mspace{14mu} {kg}\mspace{11mu} {body}\mspace{14mu} {{weight}({BW})}0.0034} = {{{Factor}\mspace{14mu} {for}\mspace{14mu} 0.0034\mspace{14mu} g\mspace{14mu} {Fe}\text{/}g\mspace{14mu} {Hb}{Hb}_{1}} = {{{Hemoglobin}\mspace{14mu} {level}\mspace{14mu} \left( {g\text{/}l} \right)\mspace{14mu} {on}\mspace{14mu} {day}\mspace{14mu} 1{Hb}_{2{(3)}}} = {{{Hemoglobin}\mspace{14mu} {level}\mspace{14mu} \left( {g\text{/}l} \right)\mspace{14mu} {on}\mspace{14mu} {day}\mspace{14mu} 8\mspace{14mu} \left( {{or}\mspace{14mu} 15} \right){BW}_{4}} = {{{body}\mspace{14mu} {weight}\mspace{14mu} (g)\mspace{14mu} {on}\mspace{14mu} {day}\mspace{14mu} 1{BW}_{9{(14)}}} = {{{body}\mspace{14mu} {weight}\mspace{14mu} (g)\mspace{14mu} {on}\mspace{14mu} {day}\mspace{14mu} 8\mspace{14mu} \left( {{or}\mspace{14mu} 15} \right){Hb}_{1\; {Control}}} = {{average}\mspace{14mu} {hemoglobin}\mspace{14mu} {level}\mspace{14mu} \left( {g\text{/}l} \right)\mspace{20mu} {on}\mspace{14mu} {day}\mspace{14mu} 1\mspace{14mu} {in}\mspace{14mu} {the}\mspace{14mu} {control}\mspace{14mu} {group}}}}}}}}}},{{Hb}_{2{(3)}\; {Control}} = {{average}\mspace{14mu} {hemoglobin}\mspace{14mu} {level}\mspace{14mu} \left( {g\text{/}l} \right)\mspace{11mu} {on}\mspace{14mu} {day}\mspace{14mu} 8\mspace{14mu} \left( {{or}\mspace{14mu} 15} \right)\mspace{14mu} {in}\mspace{14mu} {the}\mspace{20mu} {control}\mspace{20mu} {group}}},{{BW}_{4\; {Control}} = {{average}\mspace{14mu} {body}\mspace{14mu} {weight}\mspace{14mu} (g)\mspace{14mu} {on}\mspace{14mu} {day}\mspace{14mu} 1\mspace{14mu} {in}\mspace{14mu} {the}\mspace{14mu} {control}\mspace{14mu} {group}}},{{BW}_{9{(14)}\; {Contol}} = {{average}\mspace{14mu} {body}\mspace{14mu} {weight}\mspace{14mu} (g)\mspace{14mu} {on}\mspace{14mu} {day}\mspace{14mu} 8\mspace{14mu} \left( {{or}\mspace{14mu} 15} \right)\mspace{14mu} {in}\mspace{14mu} {the}\mspace{14mu} {control}\mspace{14mu} {group}}},{{{Fe}\mspace{14mu} {{Dos}.}} = {{entire}\mspace{14mu} {adminstered}\mspace{14mu} {iron}\mspace{14mu} \left( {{mg}\mspace{14mu} {Fe}} \right)\mspace{20mu} {over}\mspace{14mu} 5\mspace{14mu} {or}\mspace{14mu} 10\mspace{14mu} {days}}},{{{Fe}\mspace{14mu} {{ut}.}} = {{{\left( {{{Hb}_{2{(3)}} \cdot {BW}_{9{(14)}}} - {{Hb}_{1} \cdot {BW}_{4}}} \right) \cdot 0.07 \cdot 0.0034}\mspace{14mu} \left( {{mg}\mspace{14mu} {Fe}} \right)\Delta \mspace{14mu} {Utilization}} = {{{Fe}\mspace{14mu} {{tot}.\mspace{11mu} {utilized}}\mspace{14mu} \left( {{examined}\mspace{14mu} {group}} \right)} - {{Fe}\mspace{14mu} {{ut}.\mspace{11mu} {Control}}\mspace{14mu} {group}}}}},{{utilized}\mspace{14mu} {from}\mspace{14mu} {food}},\left( {{mg}\mspace{14mu} {Fe}} \right)} \right.}}}}}$

The following table shows the results:

TABLE Utilization n 15 d Standard deviation Example-No. (abs. %)(+/−0.5) 1 56 13 2 61 11 3 77 15 4 32 15 5 37 7 10 58 16 ComparativeExample* 25 13

*Comparative Example

As a comparative example the tris(pyridinone-2-ol-1-oxide)-iron(III)-complex compound of the formula:

was prepared in analogy to EP 0138420 and tested, to show the influenceof the heterocyclic basic structure. In Example 7 EP 0138420 disclosesonly tris(pyridinone-2-ol-1-oxide)-iron (III)-complex compounds whichcarry a further substituent at the pyridine ring. The unsubstitutedtris(pyridinone-2-ol-1-oxide)iron(III)-complex compound, which is thepresent comparative example, is not disclosed therein.

As shown in the results in the table above, the corresponding pyrimidinecompound of Example 1 of the present invention exhibits a significantlyimproved iron utilization compared to the pyridine comparative compoundin analogy to EP 0138420. The Example compounds 2, 3, 4, 5 and 10 of thepresent invention show improved iron utilization compared to thecomparative compound, too.

The measured iron utilization values are an important parameter withrespect to the indication of the treatment of iron deficiency symptomsand iron deficiency anemia, because this parameter does not only reflectthe iron adsorption but also the relation between body weight and ironadsorption, which is particularly important when using adolescentanimals in the animal model. If only the hemoglobin levels wereexamined, which are a measure for the effectively adsorbed iron, theamount which is based on the growth of the animals would remainunconsidered. Accordingly, the iron utilization is a more concretemeasure, although iron utilization and hemoglobin level mostly do notcorrelate with each other. An examination solely of the iron serumlevel, which can be measured, too, is to be less considered as therewitha prediction about the amount of iron can be given, which reaches thebody, but not about the amount thereof which can be used by the body.

The invention is further explained bby the following embodiments:

-   1. Iron(III)-pyrazine-2-ol-1-oxide complex compounds or    pharmaceutically acceptable salts thereof for the use as    medicaments.-   2. Iron(III) complex compounds according to embodiment 1, containing    at least one ligand of the formula (I):

-   -   wherein    -   the arrows respectively represent a coordinate bond to one or        different iron atoms, and    -   R₁, R₂, R₃ may be the same or different and are selected from        the group consisting of:        -   hydrogen,        -   halogen,        -   optionally substituted alkyl,        -   optionally substituted alkoxy,        -   optionally substituted aryl,        -   optionally substituted alkoxycarbonyl, and        -   optionally substituted aminocarbonyl or    -   R₂ and R₃ together with the carbon atoms to which they are        bonded, form an optionally substituted saturated or unsaturated        5- or 6-membered ring, which may optionally contain one or more        heteroatoms,    -   or pharmaceutically acceptable salts thereof.

-   3. Iron(III) complex compounds for use according to any one of    embodiments 1 to 2, containing at least one ligand of the formula    (I):

-   -   wherein    -   the arrows respectively represent a coordinate bond to one or        different iron atoms, and    -   R₁, R₂, R₃ may be the same or different and are selected from        the group consisting of:        -   hydrogen,        -   optionally substituted alkyl, and        -   halogen, or    -   R₂ and R₃ together with the carbon atoms to which they are        bonded, form a 5- or 6-membered carbocyclic ring,    -   or pharmaceutically acceptable salts thereof.

-   4. Iron(III) complex compounds for use according to any one of    embodiments 1 to 3, containing at least one ligand of the formula    (I):

-   -   wherein    -   the arrows respectively represent a coordinate bond to one or        different iron atoms, and    -   R₁, R₂, R₃ may be the same or different and are selected from        the group consisting of hydrogen and alkyl, which may optionally        be substituted by alkoxy, or    -   R₂ and R₃ together form a propylene (—CH₂—CH₂—CH₂—), butylene        (—CH₂—CH₂—CH₂—CH₂—), azabutylene or oxabutylene group,    -   or pharmaceutically acceptable salts thereof.

-   5. Iron(III) complex compounds for use according to any one of    embodiments 1 to 4, of the formula:

-   -   wherein R₁, R₂, R₃ may be the same or different and are defined        as above, and pharmaceutically acceptable salts thereof.

-   6. Iron(III)-pyrazine-2-ol-1-oxide complex compounds, as defined in    any of embodiments 1 to 5 in solid form.

-   7. Iron(III)-pyrazine-2-ol-1-oxide complex compounds according to    embodiment 6 for use as a medicament.

-   8. Iron(III)-complex compounds for use according to any one of    embodiments 1 to 5 and 7 for use in the treatment and prophylaxis of    iron deficiency symptoms and iron deficiency anemias and the    symptoms associated therewith.

-   9. Iron(III)-complex compounds for use according to embodiment 8,    wherein the symptoms include: fatigue, listlessness, lack of    concentration, low cognitive efficiency, difficulties in finding the    right words, forgetfulness, unnatural pallor, irritability,    acceleration of heart rate (tachycardia), sore or swollen tongue,    enlarged spleen, desire for strange foods (pica), headaches, lack of    appetite, increased susceptibility to infections, depressive moods.

-   10. Iron(III)-complex compounds for use according to embodiment 8    for the treatment of iron deficiency anemia in pregnant women,    latent iron deficiency anemia in children and adolescents, iron    deficiency anemia caused by gastrointestinal abnormalities, iron    deficiency anemia due to blood loss, such as gastrointestinal    hemorrhage (e.g. due to ulcers, carcinoma, hemorrhoids, inflammatory    disorders, taking of acetylsalicylic acid), iron deficiency anemia    caused by menstruation, iron deficiency anemia caused by injuries,    iron deficiency anemia due to psilosis (sprue), iron deficiency    anemia due to reduced dietary iron uptake, in particular in    selectively eating children and adolescents, immunodeficiency caused    by iron deficiency anemia, brain function impairment caused by iron    deficiency anemias, restless leg syndrome caused by iron deficiency    anemias, iron deficiency anemias in the case of cancer, iron    deficiency anemias caused by chemotherapies, iron deficiency anemias    triggered by inflammation (Al), iron deficiency anemias in the case    of congestive cardiac insufficiency (CHF; congestive heart failure),    iron deficiency anemias in the case of chronic renal insufficiency    stage 3-5 (CKD 3-5; chronic kidney diseases stage 3-5), iron    deficiency anemias triggered by chronic inflammation (ACD), iron    deficiency anemias in the case of rheumatoid arthritis (RA;    rheumatoid arthritis), iron deficiency anemias in the case of    systemic lupus erythematosus (SLE; systemic lupus erythematosus) and    iron deficiency anemias in the case of inflammatory bowel diseases    (IBD; inflammatory bowel diseases).

-   11. Iron(III)-complex compounds for use according to any one of    embodiments 1 to 5 and 7 to 10, wherein the iron(III) complex    compound is administered orally.

-   12. Iron(III)-complex compounds for use according to embodiment 11,    which is administered in the form of a tablet or a capsule,    including enteric coated forms or forms with pH-dependent coatings.

-   13. Medicament, containing iron(III) complex compounds as defined in    any one of embodiments 1 to 6.

-   14. Medicament, containing iron(III) complex compounds as defined in    any one of embodiments 1 to 6 and at least one physiological    compatible carrier or excipient.

15. Composition containing iron(III) complex compounds as defined in anyone of embodiments 1 to 6, in combination with at least one furthermedicament which acts on the iron metabolism.

1. Iron(III)-pyrazine-2-ol-1-oxide complex compounds or pharmaceuticallyacceptable salts thereof for use in the treatment and prophylaxis ofiron deficiency symptoms and iron deficiency anemias and the symptomsassociated therewith.
 2. Iron(III)-complex compounds for use accordingto claim 1, containing at least one ligand of the formula (I):

wherein the arrows respectively represent a coordinate bond to one ordifferent iron atoms, and R₁, R₂, R₃ may be the same or different andare selected from the group consisting of: hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkoxy, optionally substitutedaryl, optionally substituted alkoxycarbonyl, and optionally substitutedaminocarbonyl or R₂ and R₃ together with the carbon atoms to which theyare bonded, form an optionally substituted saturated or unsaturated 5-or 6-membered ring, which may optionally contain one or moreheteroatoms, or pharmaceutically acceptable salts thereof 3.Iron(III)-complex compounds for use according to any one of claims 1 to2, containing at least one ligand of the formula (I):

wherein the arrows respectively represent a coordinate bond to one ordifferent iron atoms, and R₁, R₂, R₃ may be the same or different andare selected from the group consisting of: hydrogen, optionallysubstituted alkyl, and halogen, or R₂ and R₃ together with the carbonatoms to which they are bonded, form a 5- or 6-membered carbocyclicring, or pharmaceutically acceptable salts thereof.
 4. Iron(III)-complexcompounds for use according to any one of claims 1 to 3, containing atleast one ligand of the formula (I):

wherein the arrows respectively represent a coordinate bond to one ordifferent iron atoms, and R₁, R₂, R₃ may be the same or different andare selected from the group consisting of hydrogen and alkyl, which mayoptionally be substituted by alkoxy, or R₂ and R₃ together form apropylene (—CH₂—CH₂—CH₂—), butylene (—CH₂—CH₂—CH₂—CH₂—), azabutylene oroxabutylene group, or pharmaceutically acceptable salts thereof. 5.Iron(III)-complex compounds for use according to any one of claims 1 to4, of the formula:

wherein R₁, R₂, R₃ may be the same or different and are defined asabove, and pharmaceutically acceptable salts thereof. 6.Iron(III)-complex compounds for use according to any one of claims 1 to5, in solid form.
 7. Iron(III)-pyrazine-2-ol-1-oxide complex compoundsfor use according to any one of claims 1 to 5, in solid form for use asa medicament.
 8. Iron(III) complex compounds for use according to anyone of claims 1 to 6, wherein the symptoms include: fatigue,listlessness, lack of concentration, low cognitive efficiency,difficulties in finding the right words, forgetfulness, unnaturalpallor, irritability, acceleration of heart rate (tachycardia), sore orswollen tongue, enlarged spleen, desire for strange foods (pica),headaches, lack of appetite, increased susceptibility to infections,depressive moods.
 9. Iron(III) complex compounds for use according toany one of claims 1 to 6 for the treatment of iron deficiency anemia inpregnant women, latent iron deficiency anemia in children andadolescents, iron deficiency anemia caused by gastrointestinalabnormalities, iron deficiency anemia due to blood loss, such asgastrointestinal hemorrhage (e.g. due to ulcers, carcinoma, hemorrhoids,inflammatory disorders, taking of acetylsalicylic acid), iron deficiencyanemia caused by menstruation, iron deficiency anemia caused byinjuries, iron deficiency anemia due to psilosis (sprue), irondeficiency anemia due to reduced dietary iron uptake, in particular inselectively eating children and adolescents, immunodeficiency caused byiron deficiency anemia, brain function impairment caused by irondeficiency anemias, restless leg syndrome caused by iron deficiencyanemias, iron deficiency anemias in the case of cancer, iron deficiencyanemias caused by chemotherapies, iron deficiency anemias triggered byinflammation (Al), iron deficiency anemias in the case of congestivecardiac insufficiency (CHF; congestive heart failure), iron deficiencyanemias in the case of chronic renal insufficiency stage 3-5 (CKD 3-5;chronic kidney diseases stage 3-5), iron deficiency anemias triggered bychronic inflammation (ACD), iron deficiency anemias in the case ofrheumatoid arthritis (RA; rheumatoid arthritis), iron deficiency anemiasin the case of systemic lupus erythematosus (SLE; systemic lupuserythematosus) and iron deficiency anemias in the case of inflammatorybowel diseases (IBD; inflammatory bowel diseases).
 10. Iron(III) complexcompounds for use according to any one of claims 1 to 9, wherein theiron(III) complex compound is administered orally.
 11. Iron(III) complexcompounds for use according to claim 10, which is administered in theform of a tablet or a capsule, including enteric coated forms or formswith pH-dependent coatings.
 12. Iron(III) complex compounds for useaccording to claim 10 or 11 for administration in the form of apharmaceutical preparation containing at least one physiologicalcompatible carrier or excipient.
 13. Composition containing iron(III)complex compounds as defined in any one of claim 1 to 6 or 12, incombination with at least one further medicament which acts on the ironmetabolism.